Sorted By Test Name - Mayo Medical Laboratories

PT11
89463
with NS and characterized by multiple lentigines and cafe-au-lait spots, facial anomalies, and cardiac
defects. Two mutations, p.Tyr279Cys and p.Thr468Met, represent the most common PTPN11 mutations
found in LEOPARD syndrome, although other mutations have been described. Mutations in PTPN11
have also been identified in patients who have clinical features of NS along with features of CFC
syndrome, a condition involving congenital heart defects, cutaneous abnormalities, Noonan-like facial
features, and severe psychomotor developmental delay. Genetic testing for PTPN11 mutations can allow
for the confirmation of a suspected genetic disease. Confirmation of NS or other associated phenotypes
allows for proper treatment and management of the disease and preconception, prenatal, and family
counseling.
Useful For: Genetic testing of individuals at risk for a known PTPN11
Interpretation: An interpretive report will be provided.
Reference Values:
An interpretive report will be provided.
Clinical References: 1. Tartaglia M, Mehler E, Goldberg R, et al: Mutations in PTPN11, encoding
the protein tyrosine phophatase SHP-2, cause Noonan syndrome. Nat Genet 2001;29:465-468 2. Tartaglia
M, Kalidas K, Shaw A, et al: PTPN11 mutations in Noonan syndrome: molecular spectrum,
genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 2002;70:1555-1563 3.
Musante L, Kehl H, Majewski F, et al: Spectrum of mutations in PTPN11 and genotype-phenotype
correlation in 96 patients with Noonan syndrome and 5 patients with cardio-facio-cutaneous syndrome.
Eur J Hum Genet 2002;11:201-206 4. Kontaridis M, Swanson K, David F, et al: PTPN11 (Shp2)
mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem
2006;281(10):6785-6792 5. Cohen MM, Gorlin RJ: Noonan-like/multiple giant cell lesion syndrome. Am
J Med Genet 1991;40:159 6. Lee JS, Tartaglia M, Gelb BD, et al: Phenotypic and genotypic
characterization of Noonan-like/multiple giant cell lesion syndrome. J Med Genet 2005;42(2):e11 7.
Tartaglia M, Gelb B, Zenker M: Noonan syndrome and clinically related disorders. Best Pract Res Clin
Endocrinol Metab 2011 Feb;25(1):161-179
PTPN11, Full Gene Sequence, Blood
Clinical Information: Noonan syndrome (NS) is an autosomal dominant disorder of variable
expressivity characterized by short stature, congenital heart defects, characteristic facial dysmorphology,
unusual chest shape, developmental delay of varying degree, cryptorchidism, and coagulation defects,
among other features. Heart defects include pulmonary valve stenosis (20%-50%), hypertrophic
cardiomyopathy (20%-30%), atrial septal defects (6%-10%), ventricular septal defects (approximately
5%), and patent ductus arteriosus (approximately 3%). Facial features, which tend to change with age,
may include hypertelorism, downward slanting eyes, epicanthal folds, and low-set and posteriorly rotated
ears. Mild mental retardation is seen in up to one-third of adults. The incidence of NS is estimated to be
between 1 in 1,000 and 1 in 2,500, although subtle expression in adulthood may cause this number to be
underestimated. There is no apparent prevalence in any particular ethnic group. Several syndromes have
overlapping features with NS, including cardiofaciocutaneous (CFC), Costello, Williams, Aarskog, and
LEOPARD (lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic
stenosis, abnormal genitalia, retardation of growth, and deafness) syndromes. NS is genetically
heterogeneous, with 4 genes currently associated with the majority of cases: PTPN11, RAF1, SOS1, and
KRAS. Heterozygous mutations in NRAS, HRAS, BRAF, SHOC2, MAP2K1, MAP2K2, and CBL have
also been associated with a smaller percentage of Noonan syndrome and related phenotypes. All of these
genes are involved in a common signal transduction pathway, the Ras-MAPK pathway, which is
important for cell growth, differentiation, senescence, and death. Molecular genetic testing identifies
PTPN11 mutations in 50% of individuals with NS. Mutations in RAF1 are identified in approximately 3%
to 17%, SOS1 approximately 10%, and KRAS less than 5% of affected individuals. NS can be sporadic
and due to new mutations; however, an affected parent can be recognized in 30% to 75% of families. The
PTPN11 gene comprises 15 exons and encodes the Src homology-2 domain-containing phosphatase
(SHP-2), a widely expressed extra-cellular protein. SHP-2 is a key molecule in the cellular response to
growth factors, hormones, cytokines, and cell adhesion molecules. It is required in several intracellular
signal transduction pathways that control diverse developmental processes. Most reported mutations in
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